5,7-pregnadiene-3-ol-20 one, esters thereof and related compounds



United States Patent 5,7-PREGNADIENE-3-OL-20 ONE, ESTERS THERE- OF AND RELATED COMPOUNDS Percy L. Julian, Maywood, John W. Cole, Oak Park, and Gerhard H. Diemer, Chicago, 111., assignors, by mesne assignments, to Chas. Pfizer & (30., inc, Broohiyn, N. Y., a corporation of Delaware Application September 17, 1949 Serial No. 116,416

12 Claims. (Cl. 260-3975) No Drawing.

that it relieves the symptoms in cases of rheumatoidarthritis. This discovery has also created interest in other 210 steroids which possess oxygenated functions at -11 as Well as at C-l2 of the steroid nucleus.

The naturally occurring C-ll oxygenated steroids are only obtained commercially by expensive procedures from limited supplies of adrenal cortices. Naturally occurring steroids containing a hydroxyl group at 0-12, such as desoxycholic acid are somewhat more plentiful but the available supplies of bile acids from which they are obtained are. also limited. The sterol-s are much more plentiful but do not possess any oxygenated function at the 6-11 or (3-12 positions. It is therefore highly desirable to provide a means whereby an oxygenated function can be introduced into C-2l steroids readily obtainable. The'introduction of a double bond in the C-ring involving the carbon atoms 9 and 11 would, however, provide an active center at the l2-position. Upon bromination of such a compound with N-bromosuccinimide, bromination at the 12-position takes placeand this is readily converted to a .l2-acyloxy group, which upon hydrolysis yields a l2-hydroxy group. T ransposition of the thus introduced 12-oxygenated group to an oxygenated function at the ll-position may then be accomplished by known means. 7

It is therefore an object to provide a process for introducing a double bond into C-Zl steroids involving the 9 and 11 carbon atoms.

Another object is to provide a process for producing pregnadieneshaving a double bond involving the 7 and 8 carbon atoms.

A further-object is to provide a process-forconverting pregnadienes having a double bond involving the 7 and 8, positions into pregnatrienes having double bonds involvingthe 7 and 8' carbon atoms and the 9 and 11 carbon atoms. 7

An additional object is to provide a process for introducing a double bond into ring C of pregnenes whereby the introduction of oxygenated functions at 0-11 or l2 is facilitated.

A still further object is to produce new. compounds useful for the production of C-21 steroids having an oxygenated function at C-1 1 or C 12.

Other objects will be apparent from the following description.

It has been found that the foregoing objects can be accomplished when esters of -pregnene-3/3-ol-20-one are hydropregnenolone acetate followed by a'n Oppenauer oxidation yields 7,9-bisdehydroprogesterone, in which it will be noted that only one double bond has migrated.

It has also been found thatwhen the 7-dehydropregnenolone ester is hydrolyzed to the free alcohol and this then subjected to an Oppenauer'oxidation that the 5-6 double bond migrates to the 4 5 position but that the" 7-8 double bond does not rnigrate. v The series of reactions may be represented by the following equations, wherein X represents an acyl group:-

Iii

Hydrolysis Oppenauer oxidation en. 7 an; i 7 i inf/J Oppenauer The following examples are illustrative:

EXAMPLE I oxidation 7-bromo-pregrienolone benzoaze Pregnenolone was benzoylefted by treating it with an equal weight of b enzoyl chloride in 10 volumes .of dry pyridine at room temperature for 12 hours. The benzoate melted at 191 C.

A solution of 15.4 g. of pregnenolone benzoate in 250 ml. of dry carbon tetrachloride was brought to refluxing, 7.7 g. of N-bromosuccinimide was added, and the isopropoxide was refluxed for two hours.

3 EXAMPLE n 7-dehydropregnenol0ne benzoate A solution of 3.1 g. of 7-bromopregnenolone benzoate m9 ml. ,of collidine was refluxed for one hour, then cooled and separated by use of ether and dilute hydrochloric acid. The washed ether solution yielded 0.9 g,

of, 7-dehydropregnenolone benzoate, M. P. 217-218". Additional material was obtained from the mother liquor. Analysis.-Calcd. for C H O z C, 80.34; H, 8.19. Found: C, 80.21 ;H, 8.01. o

EXAMPLE III 7-dehydropr egnenolone 7 Three grams of the 7-dehydropregnenolone benzoate in 70 ml. of benzene was hydrolyzed under nitrogen by re fluxing for 30 minutes with 170 ml. of 5% potassium hydroxide in methanol. The 7-dehydropregnenolone crystallized from ether petroleum ether, M. P. 224-225. Analysis.-Calcd. for 0, 11, 0 C, 80.22; H, 9.60. Found: C, 79.82; H, 9.34.

EXAMPLE IV '7-dehydroprogesterone A mixture of 0.9 g. of 7-dehydropregnenolone, 48 ml.

of toluene, 3 m1. of cyclohexanone, and 1.2 g. aluminum isopropoxide was refluxed for two hours. The cooled reaction product was diluted with ether, washed several times with 10% sulfuric acid, and then with dilute alkali and with water. The ether solution yielded 0.36 g. of 7-dehydroprogesterone, M. P. 115-117"; U. V. E 17,300 at 240 m Analysis.Calcd. for C H O C, 80.72; H, 9.02. Found: C, 80.81; H, 9.12.

EXAMPLE V 7,9-bisdehydropregnenolone benzoate Twoand one-half grams of 7-dehydropregnenolone benzoate in 25 ml. of dry chloroform was treated with 4 g. of mercuric acetate in 55 ml. of acetic acid with stirring for.1 8 hours. The solution was filtered and concentrated. The 7,9-bisdehydropregnenolone benzoate (1.3 g.) crystallized from methanol melted at 195-196; U. V. maxima at 228 m and 324 m Analysis.-Calcd. for C H O C, 80.75; H, 7.60. Found: C, 80.23; H, 7.70.

EXAMPLE VI 5,7,9-pegnatriene-3fi-0Z-20-one Two and one-half grams of the 7,9-bisdehydropregnenolone benzoate were hydrolyzed in 50 ml. of benzene with 60 ml. of 5% potassium hydroxide in methanol by refluxing the mixture for one hour. The product separated from ether-petroleum ether as 1.5 g. of white crystals, M. P. 205- Analysis.Calcd. for C H O C, 80.72; H, 9.03. Found: C, 80.50; H, 9.12.

EXAMPLE VII 4,7,9-pregnatriene-3,20-di0ne A mixture of 1.1 g. of 5,7,9-pregnatrienolone, 50 ml. of toluene, 6 ml. of cyclohexanone, and 3 g. of aluminum The cooled solution was separated with benzene and 10% sulfuric acid. The cyclohexanone and solvents were removed by brief steam distillation, and the product was separated and crystallized from methanol as plates, M. P. 157-158"; U. V.single maxima at 242 my.

AMIYSiS-C31Cd.' for cg Hzaozi C, H, 8.45-

' Found: C, 81.07; H, 8.62.

In the foregoing examples the benzoate has been employed. However, other esters, such as the acetate, propionate, etc., may be used. Also, other tertiary amines may be used for the dehydrobromination. Likewise, other ketones, such as acetone, and other aluminum alkoxides may be used in the Oppenauer oxidation.

As previously indicated the 7,9-bisdehydroprogesterone.

may be treated with N-bromosuccinimide to form the 7,9-bisdehydro-12-bromo-progesterone, and this then converted into the 12-acyloxy derivative and then to the l2-hydroxy derivative. The conjugated double bond system may then be reduced.

Conversion of the 12-hydroxy compound into an 11- oxygenated derivative may, if desired, then be efl'fected in a manner known to the art.

It is thus seen that a procedure is provided which makes the abundant steroids available for theproduction of C-21 .steroids possessing an oxygenated functionat the C-11 or C-12 positions, the starting materials, of course, being readily available from such materials as soya sterols, diosgenin, etc.

Having described the invention, what is claimed is:

1. The process which comprises treating an ester' of 5-pregnene-3-ol-20-one with N-bromosuccinimide to form they 7-bromo derivative, dehydrobrominating the resulting bromo derivative by treatment with a tertiary amine,-

treating the resulting 5,7-pregnadienolone ester with mercuric acetate in the presence of acetic acid to form the 5,7,9-pregnatrienolone ester, hydrolyzing the thus formed ester, and subjecting the resulting free alcohol to an Oppenauer oxidation to form 4,7,9-pregnatriene-3,20- dione.

2. The process which comprises treating an ester'of 5-pregnene-3-ol-20-one with N-bromosuccinimide to form the 7-bromo derivative, dehydrobrominating the resulting bromo derivative by treatment with a tertiary amine, and treating the resulting 5,7-pregnadienolone ester with mercuric acetate in the presence of acetic acid to form the 5,7,9-pregnatrieneolone ester.

3. The process of claim 2 in which the ester is the References Cited the file of this patent UNITED STATES PATENTS Oppenauer Sept. 4, 1945 Vliet et a1. May 4,.1948

OTHER REFERENCES Windaus: Annalen 465, pages 157, 158 (1928).

Windaus: Berichte 70, pages 379 (1937).

Heilbron: J. Chem. 800., page 1223 (1935).

Newer Methods of Preparative Organic Chem., Interscience Publishers, pages 143-154 (1948). 

5. 4,7,9-PREGNATRIENE-3,20-DIONE.
 8. COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF 5,7-PREGNADIENE-3-OL-20-ONE AND ESTERS THEREOF WITH A HYDROCARBON CARBOXYLIC ACID CONTAING NOT MORE THAN 7 CARBON ATOMS. 